Project Summary Risk of cardiovascular diseases (CVD) is significantly elevated in patients with chronic kidney disease (CKD); however, this increased risk is only partially explained by traditional CV risk factors. Arterial dysfunction is an important nontraditional CV risk factor gaining increased recognition in the field of nephrology. While many changes likely contribute to the development of arterial dysfunction in patients with CKD, among those of greatest concern is the development of stiffening of the large elastic arteries. This process is best represented, both physiologically and pathophysiologically, by increases in the gold standard measure of arterial stiffening, carotid to femoral artery pulse wave velocity (CFPWV), which reflects, in particular, increases in aortic stiffness. Aortic stiffening with CKD is mediated by structural and functional (increased vascular smooth muscle tone) changes in the arterial wall stimulated by oxidative stress and chronic low-grade inflammation. Caloric restriction (CR) is a promising strategy for prevention of CKD-associated arterial dysfunction and CVD. In this context, we have shown that CR reduces CFPWV and SBP in older mice and in overweight/obese middle-age and older adults. However, long-term adherence to chronic CR regimens with optimal nutrition is very difficult to achieve and unlikely to become clinically relevant in the near future as it may reduce muscle and bone mass. As a result, we have since shown that boosting NAD+ bioavailability to stimulate SIRT-1, a ?CR mimetic? approach, reduces CFPW and oxidative stress in old mice, and we recently took the first step in translating these findings in a study of middle-age and older adults with normal kidney function and elevated systolic blood pressure (SBP). We found that supplementation with nicotinamide riboside, a natural, commercially available precursor of NAD+ and novel CR mimetic, was well tolerated and increased NAD+ bioavailability and reduced CFPWV and SBP. Here we propose a randomized, placebo- controlled, double-blind, single-site phase IIa clinical trial to assess the safety and efficacy of oral nicotinamide riboside (500 mg capsules 2x/day; NIAGEN; ChromaDex Inc.) for 3 months vs. placebo (n=59/group) for decreasing aortic stiffness and SBP in men and women (35-80 years) with stage III and IV CKD. We hypothesize that treatment will be safe and well-tolerated, and will reduce CFPWV and SBP, as related to increases in systemic NAD+ bioavailability and reductions in oxidative stress, inflammation and vasoconstrictor factors. Aim 1: To measure CFPWV (primary outcome) before/after nicotinamide riboside vs. placebo treatment; Aim 2: To measure casual and 24h-ambulatory SBP (secondary outcome) before and after treatment; Aim 3: To determine the safety and tolerability of treatment with nicotinamide riboside vs. placebo; Aim 4: To measure systemic NAD+ and NAD+?related metabolite concentrations, as well as circulating markers of oxidative stress, inflammation, and vasoconstriction factors before and after treatment.